Antisense therapy involves the administration of exogenous oligonucleotides that bind to a target nucleic acid, typically an RNA molecule, located within cells. The term antisense is so given because the oligonucleotides are typically complementary to mRNA molecules ("sense strands") which encode a cellular product. The ability to use anti-sense oligonucleotides to inhibit expression of mRNAs, and thereby to inhibit protein expression in vivo, is well documented. However, selection of an appropriate complimentary oligonucleotide (or oligonucleotides) to a given mRNA is not always simple (see, e.g., Crooke, S. T. FASEB J. 7: 533-539 (1993), incorporated herein by reference). Anti-sense agents typically need to continuously bind all target RNA molecules so as to inactivate them or alternatively provide a substrate for endogenous ribonuclease H (Rnase H) activity. Sensitivity of RNA/oligonucleotide complexes, generated by the methods of the present invention, to Rnase H digestion can be evaluated by standard methods (see, e.g., Donia, B. P., et al., J. Biol. Chem. 268 (19):14514-14522 (1993); Kawasaki, A. M., et al., J. Med. Chem. 6(7):831-841 (1993), incorporated herein by reference).